In 2013, the National Cancer Institute (NCI) awarded a five-year, $11.3 million Specialized Program of Research Excellence (SPORE) grant (CA168505) to The Ohio State University in collaboration with MD Anderson Cancer Center in Houston, TX.
Matthew Ringel, MD, co-director of the Thyroid Cancer Unit at Ohio State and a physician-researcher at the OSUCCC – James Molecular Biology and Cancer Genetics Program, is the lead for the Thyroid Cancer SPORE grant.
The primary goal of The Ohio State University/MD Anderson Thyroid Cancer SPORE is to improve the outcomes and lives of patients with thyroid cancer by identifying genetically "at-risk" individuals to allow for early diagnosis and prediction of tumor behavior.
The grant supports four interactive research projects and three core services. The work focuses on critical questions and rapidly translating the answers into improved care for people with thyroid cancer. It will also develop new approaches for minimizing treatment side effects, and it will identify better biomarkers and treatment options for progressive metastatic disease. If successful, the research will improve thyroid cancer detection, treatment, management and monitoring.
Why This Effort is Needed
Thyroid cancer incidence is rising faster than any other malignancy in the United States and worldwide; it is now the 5th most common malignancy in women and 11th most common in men in the US.
Thyroid cancer typically takes an indolent course when diagnosed early. This, plus increasing incidence, is producing an ever-enlarging population of long-term survivors (about 600,000), many of whom suffer lifelong effects of initial therapy.
Aggressive forms of thyroid cancer, such as medullary cancer (MTC), lack no curative therapies or biomarkers that accurately predict death from disease or response to particular treatments.
Thyroid Cancer SPORE Projects
The Thyroid Cancer SPORE grant consists of four interactive research projects.
Project 1: Low-penetrance genes in the predisposition to papillary thyroid carcinoma (PTC)
Project Leaders: Albert de la Chapelle, MD, PhD; Rebecca Nagy MS, CGC
These researchers are working to firmly identify genes associated with PTC predisposition, determine the biological functions of identified risk mutations and determine if they predict thyroid cancer risk and tumor behavior in patients with PTC.
The investigators have already published that several genomic markers (SNPs) are highly associated with PTC, including two genome-wise association studies that involve large patient populations with apparently sporadic disease. Candidate genes have been identified. A concept is emerging that long intergenic noncoding RNA genes (lincRNAs) are major players in thyroid cancer susceptibility, but the mechanisms involved are unknown.
Project 2: Biomarker Discovery and Personalized Intervention of Radioiodine Induced Salivary Gland Damage in Thyroid Cancer Patients
Project Leaders: Sissy Jhiang, PhD; Ricardo Carrau, MD
This project seeks to improve the quality of life for long-term thyroid cancer survivors by developing novel approaches to eliminate or reduce salivary gland damage from radioactive iodine therapy.
A common therapy for thyroid cancer uses I-131. Patients receiving the treatment often experience long-term survival. Unfortunately, this treatment permanently damages the salivary glands in up to 30 percent of treated patients, causing lifelong pain, dry mouth, taste disturbances and dental damage. It is now recognized that the previous standard preventive measures may worsen this side effect.
Using case-control and prospective studies, Project 2 will determine the best strategies for predicting and preventing this damage, develop and test new biomarkers that predict a likelihood of salivary gland dysfunction, and develop new therapies to prevent this difficult survivorship problem.
Project 3: Developing Combination Therapies for Medullary Thyroid Cancer
Project Leaders: Matthew Ringel, MD; Manisha Shah, MD
Project 3 is designed to improve treatments for patients with progressive medullary thyroid cancer (MTC).
MTC metastasizes earlier than other forms of differentiated thyroid cancer, and it accounts for a disproportionate amount of disease-related mortality. Treatment with multikinase inhibitors induces stable disease or non-durable partial remissions in about 50 percent of patients. Recently, the FDA approved vandetanib and cabozantinib for treating patients with metastatic progressive MTC. However, patients require lifelong treatment and acquire resistance, creating the critical need for new second line therapies.
This project will identify strategies to treat resistant MTC. A focused Phase II clinical trial will be performed based on an observed synergy of targeting RET, RAF, and MEK. Additional studies will identify pathways of resistance using state-of-the-art genetic and proteomic approaches. A third approach will be to target cyclin-dependent kinases, which play a role in MTC development and progression in vivo.
Project 4: Development and Validation of Novel Circulating Medullary Thyroid Cancer Markers
Project Leaders: Gilbert Cote, PhD; Steven Sherman, MD
The goal of Project 4 is to develop new biomarkers to assess medullary thyroid cancer (MTC) progression, drug resistance, and early recurrence. The early identification of distant metastases and understanding the biological properties of metastasizing cells remain a challenge in MTC.
Project 4 will test several approaches to enhance detection of MTC progression using cell-free DNA assays and circulating tumor cell (CTC) detection. The proposal builds upon the discovery of a MTC cancer stem cell subpopulation and the identification of cell-specific transcripts (PROM1, NKX2.2. and SOX2), that are upregulated by vandetanib treatment.
Thyroid Cancer SPORE Cores
Three core services support the Thyroid Cancer SPORE projects. The cores involve both the OSUCCC – James and MD Anderson (MDACC) and integrate their efforts.
Core A: Integrated Clinical Information and Pathology Sample Repository
Co-Leader: John Phay, MD, OSUCCC – James; Rebecca Nagy, MS, CGC, OSUCCC – James; Adel El-Naggar, MD, MDACC
The Integrated Clinical Information and Pathology Sample Repository Core provides high-quality clinical data and subject samples for the Thyroid Cancer SPORE research projects. It uses and is expanding the clinical and biospecimen resources that already exist at both institutions.
In addition to biological samples from thyroid cancer patients, the core stores corresponding clinical, pathology and family history data that is entered into a relational database. When projects require additional or different samples or data, the core prospectively collects it.
Core A Aims:
- Provide sound clinical and pathological information to SPORE research activities that use human samples are provided with.
- Ensure that data are efficiently and accurately managed.
- Distribute samples and data in a reliable and timely manner.
Core B: Biostatistics Core
Leader: Soledad Fernandez, PhD
Core B provides biostatistical and bioinformatics analysis support to the Thyroid Cancer SPORE research projects, and to developmental research projects and career development projects.
Dr. Fernandez directs the OSUCCC – James Biostatistical Shared Resource and leads a team of statisticians skilled in specific types of analyses.
- Core members assist in the design of Thyroid Cancer SPORE laboratory and clinical experiments to help ensure robust and rigorous hypothesis testing.
- The core performs all statistical analyses for all projects at both sites to provide full integration and analytical consistency.
Core C: Administrative Core
Leader: Matthew D. Ringel, MD, OSUCCC – James
Co-Leader: Gilbert Cote, PhD, MDACC
Core C works to ensure the integration of SPORE activities and to facilitate the success of the individual projects and components.
Administrative Core Aims:
- Arrange an annual meeting of SPORE investigators to advance scientific exchange, component review, investigator interactions, and progress review. The meeting includes the internal and external SPORE Advisory Boards.
- Assist with budget reviews and analysis to ensure efficient and appropriate use of funds.
- Organize and maintain a secure website and arrange regular multi-site teleconferences and web-based presentations.
- Assist the Developmental Research and Career Development Programs.
- Facilitate interactions between project and core leaders and co-leaders at both the OSUCCC – James and MDACC.
Development Research Program
Project Leader: Sissy Jhiang, PhD
Co-Leader: Steven Sherman, MD
The Development Research Program (DRP) is a source of new innovative projects that can replace SPORE projects that are completed or that have not fulfilled specific translational expectations. It also infuses the Thyroid Cancer SPORE with new ideas, resources and technologies that drive translational research.
To carry out its mission, the DRP solicits proposals and provides funding for high-risk, high-impact pilot projects that explore new ideas and that are likely to eventually improve thyroid cancer prevention, diagnosis, prognosis and therapeutics.
- Develop a rigorous process to advertise the available resources of the SPORE and solicit proposals from investigators with broad expertise;
- Define a rigorous peer-review process to select meritorious proposals and to monitor annual progress of funded proposals;
- Assist funded proposals develop into full SPORE projects or into nationally funded independent grant applications.
The DRP expects to fund two new proposals in year 1 and year 3, and one new proposal in years 2, 4, and 5.
Career Development ProgramProject Leader: Lawrence Kirschner, MD, PhD
Co-Leader: Robert Gagel, MD
The Thyroid Cancer SPORE Career Development Program (CDP) is designed to attract and mentor talented junior translational scientists and clinicians to the field of thyroid cancer research. These young researchers will be encouraged to discover and apply new approaches to understanding the etiology and epidemiology, prevention, diagnosis, treatment and cure of thyroid cancer.
Success of the CDP will be judged by the quality of the science generated by the awardees, their success in obtaining external peer-reviewed funding, their success in academic advancement, and their retention in academia and translational research in thyroid cancer.
The CDP is led by two senior translational researchers who have a history of commitment to academic education and mentorship in leadership positions at their home institutions.
- Dr. Lawrence Kirschner is associate director of the MD/PhD Medical Scientist Program at Ohio State and past director of the Endocrinology, Diabetes, and Metabolism fellowship program. He has served on the Department of Internal Medicine internship committee, College of Medicine curriculum development committee, and Institutional Graduate Medical Education committee.
- Dr. Robert Gagel, program co-leader at MDACC, currently heads MDACC’s Division of Internal Medicine. Prior to that, he was chairman of the MDACC Endocrine Department. He has mentored a large number of young postdoctoral researchers, clinical fellows, and young faculty members.